By Christina Towers, PhD.
Autophagy mediates the recycling of damaged cellular material into building blocks like amino acids and other necessary nutrients that can fuel metabolism and cell growth, especially under nutrient depleted conditions. There are currently over 60 clinical trials reported on ClinicalTrials.gov that are either completed or on-going using autophagy inhibition, mostly in combination with other targeted therapies. Autophagy has a pro-tumorigenic role in established tumors and consequently the vast majority of clinical trials focus on autophagy inhibition in cancer. Over the last decade, a dozen Phase I and I/II clinical trials have been completed and published using the autophagy inhibitors, Chloroquine (CQ) or hydroxychloroquine (HCQ) in cancer. These lysosomal targeting compounds were originally approved for use in humans as anti-malarial drugs but have been repurposed as autophagy targeting cancer therapeutics.
Immunohistochemistry-Paraffin: Beclin 1 Antibody [NB110-87318] - IHC analysis of a formalin fixed paraffin embedded (FFPE) tissue section of human breast cancer using Beclin 1 antibody Lot F4 at 1:300 dilution. The primary antibody bound to Beclin 1 antigen in the tissue section was detected using a HRP labeled secondary antibody and DAB reagent. Nuclei of the cells were counterstained with hematoxylin. This Beclin 1 antibody generated cytoplasmic staining in the cancer as well as the stromal cells. The signal was strongest in a subset of stromal cells which appears to be the cancer associated fibroblasts.
Published Clinical Trials:
During the first wave of Phase I/II clinical trials a breadth of knowledge was achieved1. These initial studies included pharmacokinetic-pharmacodynamic assays proving that the FDA approved doses for CQ/HCQ could cause an observable decrease in autophagy in tissues and that these drugs either alone, or in combination with other targeted therapies were well tolerated in most patients. One study conducted in patients with refractory solid tumors tested the combination of HCQ and the histone deacetylase inhibitor, Vorinostat, and found that 5 out of 19 patients maintained prolonged stable disease2. A phase I/II study in pancreatic cancer patients examined the neoadjuvant combination of HCQ and the antimetabolite, Gemcitabine, and found the combination to be safe and tolerable in this setting with promising neoadjuvant activity3.
These results have led to the launch of two additional randomized Phase II studies in pancreatic cancer with HCQ and Gemcitabine1. Encouraging results have also been seen in lung and breast cancer patients with brain metastasis where the addition of CQ resulted in a one-year brain metastasis progression-free survival in 83% of patients compared to 53% in the placebo arm4. Likewise, in a dose escalating study in melanoma, combination of HCQ with the alkylating agent, Temazolomide, caused 14 of the 17 patients enrolled on this arm to achieve stable disease5. Improved phase II studies have now been launched with more effective targeted therapy combinations and meeting abstracts suggest some of these trials may show promise for specific tumor types1.
Overall these studies and many others have demonstrated tolerable and effective doses for CQ and HCQ with minimal side effects and have shown some promising therapeutic benefit. However, these results have also revealed room for improvement with autophagy inhibition. It is clear that some patients may benefit more than others, and reliable biomarkers are necessary to screen patients prior to treatment. Moreover, autophagy inhibitors with more potency and specificity are needed. To this end, Lys056 and DQ6617 have recently been identified as autophagy inhibitors that are 10 fold more potent than chloroquine in vitro and in pre-clinical animal models. Clinical trials with these compounds should be underway soon and the field is anticipating even more promising results.
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Christina Towers, PhD
University of Colorado (AMC)
Dr. Towers studies the roles of autophagy, apoptosis and cell death in cancer.
- Onorati, A. V., Dyczynski, M., Ojha, R. & Amaravadi, R. K. Targeting autophagy in cancer. Cancer, doi:10.1002/cncr.31335 (2018).
- Patel, S. et al. Vorinostat and hydroxychloroquine improve immunity and inhibit autophagy in metastatic colorectal cancer. Oncotarget, doi:10.18632/oncotarget.10824 (2016).
- Wolpin, B. M. et al. Phase II and pharmacodynamic study of autophagy inhibition using hydroxychloroquine in patients with metastatic pancreatic adenocarcinoma. Oncologist 19, 637-638, doi:10.1634/theoncologist.2014-0086 (2014).
- Rojas-Puentes, L. L. et al. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases. Radiation oncology 8, 209, doi:10.1186/1748-717X-8-209 (2013).
- Rangwala, R. et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 10, 1369-1379, doi:10.4161/auto.29118 (2014).
- McAfee, Q. et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency. Proc Natl Acad Sci U S A 109, 8253-8258, doi:10.1073/pnas.1118193109 (2012).
- Rebecca, V. W. et al. A unified approach to targeting the lysosome's degradative and growth signaling roles. Cancer Discov, doi:10.1158/2159-8290.CD-17-0741 (2017).